Mixed Connective Tissue Disease (MCTD) 

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Overview

MCTD is a systemic autoimmune rheumatic disease characterized by overlapping clinical features of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis, with rheumatoid arthritis with high titres of anti-U1 RNP antibodies. It typically affects women aged 20–40 years. Prevalence is estimated at 3.8 per 100,000; more common in females (F:M ~9:1). The disease course may evolve toward a predominance of one specific connective tissue disease phenotype over time.

Definition

Mixed Connective Tissue Disease (MCTD): A distinct autoimmune condition with overlapping features of SLE, SSc, and polymyositis, and high anti-U1 RNP antibodies.
Anti-U1 RNP antibodies: Autoantibodies targeting U1 small nuclear ribonucleoprotein complex; hallmark of MCTD.
Raynaud’s phenomenon: Episodic digital ischemia triggered by cold/stress causing triphasic color change (white-blue-red).

Aetiology and Risk Factors

Aetiology

  • Autoimmune dysregulation with production of high-titre anti-U1 RNP antibodies.
  • Likely multifactorial: genetic predisposition, hormonal influence, and environmental triggers.

Risk Factors

  • Female sex
  • Age 20–40
  • HLA-DR4 and HLA-DR2 alleles
  • Family history of autoimmune disease.

Pathophysiology

  • Trigger (e.g. infection or environmental antigen) leads to immune dysregulation.
  • Overproduction of autoantibodies—especially anti-U1 RNP.
  • Immune complexes deposit in target tissues → complement activation → inflammation.
  • Chronic inflammation leads to fibrosis (especially pulmonary and dermal) and vascular damage (Raynaud’s).

Anti-U1 RNP not only aids in diagnosis but may drive immune complex deposition and systemic effects.

Clinical Manifestations

Common Features mixture or overlap of the following:

  • SLE
    • Photosensitive rash
  • Systemic sclerosis
    • Pulmonary involvement (interstitial lung disease, pulmonary hypertension)
    • Raynaud’s phenomenon (often earliest sign)
    • Puffy/swollen hands (“sausage digits”)
    • Esophageal dysmotility (dysphagia, reflux)
    • Sclerodactyly and telangiectasia
  • Rheumatoid arthritis
    • Arthralgia/arthritis (similar to RA, but non-erosive)
  • Inflammatory myopathy
    • Proximal muscle weakness

Systemic Symptoms

  • Fatigue, low-grade fever, weight loss

Diagnosis

Diagnostic Criteria (Alarcón-Segovia, 1987 – widely used):

  • Positive anti-U1 RNP antibodies (high titre)
  • At least 3 of the following:
    • Raynaud’s phenomenon
    • Swollen hands
    • Synovitis
    • Myositis
    • Acrosclerosis

Investigations:

  • ANA (usually positive, speckled pattern)
  • Anti-U1 RNP (high titre)
  • ESR/CRP (elevated)
  • Creatine kinase (↑ if myositis)
  • Pulmonary function tests (↓ DLCO in ILD or PH)
  • HRCT chest (for ILD)
  • ECG/Echo (screen for pulmonary hypertension)

Differential Diagnoses:

ConditionDifferentiating Features
SLEdsDNA, anti-Sm, renal involvement more prominent
Systemic sclerosisScl-70, diffuse skin thickening
PolymyositisNo Raynaud’s or sclerodactyly
RAErosive arthritis, anti-CCP positivity

Remember

High anti-U1 RNP titre with overlapping features is diagnostic and may correlate with disease activity.

Remember

Always screen for pulmonary hypertension in MCTD patients with breathlessness or abnormal PFTs

Treatment

  • Individualized based on predominant features.

Mild disease (arthralgia, Raynaud’s):

  • NSAIDs
  • Hydroxychloroquine
  • Nifedipine for Raynaud’s

Moderate-to-severe disease:

  • Corticosteroids (e.g. prednisolone 0.5–1 mg/kg for myositis or ILD)
  • DMARDs (methotrexate, azathioprine, mycophenolate)
  • Rituximab (if refractory or ILD)
  • PPI and prokinetics for esophageal symptoms

Pulmonary hypertension: endothelin receptor antagonists, sildenafil.

Complications and Prognosis

Complications

  • Interstitial lung disease (most common and serious)
  • Pulmonary hypertension (common)
  • Secondary Sjögren’s syndrome

Prognosis

  • 10-year survival >80% with treatment
  • Pulmonary hypertension = major cause of mortality

Poor Prognostic Factors

  • Severe ILD or pulmonary hypertension
  • Cardiac involvement

High corticosteroid requirement.

References

  1. Sharp GC et al. Autoantibodies to ribonucleoprotein in MCTD. Arthritis Rheum. 1972;15(6):629-35.
  2. Alarcón-Segovia D et al. Mixed connective tissue disease: An overview. Rheum Dis Clin North Am. 2005;31(3):605-23.
  3. Gunnarsson R et al. Mixed connective tissue disease criteria review. Scand J Rheumatol. 2005;34(1):48–53.
  4. Greidinger EL. Advances in the understanding of MCTD. Curr Rheumatol Rep. 2015;17(7):39.
  5. Burdt MA et al. Long-term outcomes of MCTD. Medicine (Baltimore). 1999;78(6):378-90.

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